Details

Autor(en) / Beteiligte

• Tsai, Ping-Hsing
• Chien, Yueh
• Wang, Mong-Lien
• Hsu, Chih-Hung
• Laurent, Benoit
• Chou, Shih-Jie
• Chang, Wei-Chao
• Chien, Chian-Shiu
• Li, Hsin-Yang
• Lee, Hsin-Chen
• Huo, Teh-Ia
• Hung, Jui-Hung
• Chen, Chung-Hsuan
• Chiou, Shih-Hwa

Titel

Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network

Ist Teil von

• Nucleic acids research, 2019-11, Vol.47 (19), p.10115

Ort / Verlag

England

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l-Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.